CN101628086B - Gastrodiaelata Blume plant extract for preventing and treating vascular dementia and preparation method thereof - Google Patents
Gastrodiaelata Blume plant extract for preventing and treating vascular dementia and preparation method thereof Download PDFInfo
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Abstract
The invention relates to application of a Gastrodiaelata Blume plant extract containing parishin derivants on preparing a medicament for preventing and treating vascular dementia and other diseases. The invention also relates to a method for preparing the plant extract extracted and refined from Gastrodiaelata Blume plant, wherein active components are the parishin derivants, in particular to parishin A, B and C. The method adopts alcohol extraction; and an extract is refined and purified by a chromatogram method to obtain the plant extract with the content of the parishin derivants of 35 percent, in particular over 50 percent. A medicament preparation optimally selects injections, troches, capsules, soft capsules, oral liquid or dropping pills and the like.
Description
Technical field
The invention belongs to natural medicine technical field.Be specifically related to a kind of purposes of Rhizoma Gastrodiae (Gastrodia elata Blume) plant extract in the medicine of preparation treatment of vascular dementia disease that contains parishin A, B, C and/or its derivant.From the Chinese medicine Rhizoma Gastrodiae, extract, make with extra care the plant extract and the method for distilling thereof that obtain.
Background technology
Modern life style causes that Patients with Vascular Dementia increases day by day, and modern medicine study thinks that vascular dementia (VD) is a multi-factor disease, and is relevant with atherogenic factors such as hypertension, diabetes, hyperlipidemia.Most scholars think, the normal and cortex pathological changes of the generation of vascular dementia, and especially the ischemia of left side cortex ischemia and thalamus, Hippocampus changes closely related.In addition, bilateral, multiple cerebral infarction, the ischemia infraction and large tracts of land cerebral lesion the playing an important role of critical positions to primary disease.Not only the incidence and development of apoplexy and VD have close cause effect relation, and long-term chronic brain ischemia also can cause the generation of VD.
Vascular dementia patient generally can't take care of oneself, and needs the household to take care of constantly, brings white elephant for patient, family, society.Pharmaceutically active ingredient in from the higher Chinese crude drug of known safety, extracting, development and exploitation new Chinese medicine are necessary.
Rhizoma Gastrodiae another name RHIZONA GASTRODIAE, Bai Longcao, rhizoma gastrodiae root.Tuber for the perennial parasitic herbaceous plant Rhizoma Gastrodiae Gastrodia elata Blume of the orchid family.Perennial plant is born in moistening sylvan life, existing many cultivations.Mainly originate from ground such as Sichuan, Yunnan, Guizhou, Hubei and Shaanxi in China.Rhizoma Gastrodiae is mainly used in endogenous wind stopping relieving convulsion, suppressing the hyperactive liver and subsiding YANG, wind-expelling pain-stopping and migraine and general headache etc. in Chinese medicine.
Pai Lixin (parishin) is a kind of main chemical compositions in the plant Rhizoma Gastrodiae, and document 1-5 has reported that the structure of Pai Lixin (parishin) A, B, C is following:
Wherein, abbreviate Pai Lixin (parishin) usually as in the former document of parishin A (parishin A), for to distinguish, be referred to as parishin A (parishin A) among this paper with two other known Pai Lixin compounds (parishin B, C).
List of references:
1、Li?Y.M.，Zhou?Z.l.，Hong?Y.F.New?pheno?lic?derivativesfrom?Galeola?faberi.?Plan?ta?Med.1993，59(4)：363-5。
2、Lin?J.H.，Liu?Y.C.，Hau?J.P.，et?al.?Parishins?B?and?Cfrom?rhizomes?of?Gastrodia?elata.Phytochemis?try，1996，42(2)：549-551。
3, Zhou Jun, Chongqing, Hunan, Pu, Yang Yanbin.Nine kinds of phenolic constituents of fresh gastrodia elata.Science Bulletin, 1981,26 (18): 1118-1120.
4、Dahmen?J.，Leander?K.?Studies?on?Orchidaceae?glucosides.Part?7.The?structure?of?parishin，a?glucoside?from?Vandaparishii.Phytochemistry，1976，15(12)：1986-7。
5、Taguchi?H.，Yosioka?I.，Yamasaki?K.，et?al.Studies?onthe?constituents?of?Gastrodia?ela?ta?Blume.Chem.Pharm.Bull.，1981，29(1)：55-62。
Although bibliographical information carry out the repeated multiple times chromatographic isolation through positive and reverse phase silica gel, obtain the method for the monomeric compound of Pai Lixin derivant, reported never that these monomeric compounds were relevant with the effect of treatment of vascular dementia.
Because complex chemical composition in the Rhizoma Gastrodiae; And Pai Lixin compounds polarity has than big difference; Utilize single chromatographic separation technology enrichment high-load (greater than 50%) the Pai Lixin derivant that is fit to suitability for industrialized production that big difficulty is arranged; Also there is not bibliographical information to obtain the Blume plant extract of the Pai Lixin derivant of high-load (greater than 50%) at present; Do not report the method for utilizing chromatographic separation technology to realize preparing the Blume plant extract that is rich in its derivant of Pai Lixin yet, found never that containing the Blume plant extract of Pai Lixin derivant or the monomeric compound of Pai Lixin derivant (particularly parishin A, B, C) or mixture had the intelligence of increasing and the effect of treatment of vascular dementia yet.
Summary of the invention
The invention provides the Blume plant extract or Pai Lixin monomeric compound or the purposes of mixture in the medicine of diseases such as preparation treatment of vascular dementia that contain Pai Lixin derivant (particularly parishin A, B, C).Wherein Pai Lixin derivant total content is more than 35% in this extract, and preferred Pai Lixin derivant total content is the extract more than 50%.Monomer, particularly parishin A, B, C arbitrarily in the said Pai Lixin derivant Ke Yi Wei Pai Lixin derivant, the also mixture of any multiple monomeric compound in the Ke Yi Wei Pai Lixin derivant.
Logical at present pharmacodynamic experiment result shows that each dose groups of Rhizoma Gastrodiae effective site can improve to some extent intends vascular dementia model learning and memory in rats ability, alleviates the europathology damage of rat model.Its possible effect link comprises: 1. effectively induce the synthetic of neure growth GAP-associated protein GAP in the brain injury repair process, suppress the hyper-proliferative of astrocyte, promote neurite regeneration behind the cerebral ischemia.2. the neuronic synaptic activity of regulating and control to degenerate of glutamic acid; Rebuild 4. anti peroxidation of lipid of function that 3. Glu/GABA learning and memory regulating system stable state in the brain improve cholinergic system in the brain; It is active to activate free radical resisting oxidase SOD, accelerates the clearance rate of cerebral tissue free radical, reduces the accumulation of Radical Metabolism product MDA; Compare with the positive control drug donepezil of a present line, drug effect is superior to donepezil.The plant extract that shows the monomeric compound or the mixture of Pai Lixin derivant and contain Pai Lixin derivant (particularly parishin A, B, C) has the effect of treatment of vascular dementia.
Said " monomer " is defined as the unification compound.
The present invention also provides a kind of Blume plant extract of the Pai Lixin of containing derivant; Pai Lixin derivant total content is more than 35% in this extract; Preferred Pai Lixin derivant total content is more than 50%; More preferably Pai Lixin derivant total content is 50%-95%, and preferred said Pai Lixin derivant is parishin A, B, C.
The present invention also provides a kind of preparation to contain the method for Pai Lixin derivant plant Rhizoma Gastrodiae extract; Wherein Pai Lixin derivant total content is more than 35% in the extract; Preferred Pai Lixin derivant total content is more than 50%; More preferably Pai Lixin derivant total content is 50%-95%, and preferred said Pai Lixin derivant is parishin A, B, C.
Through our research, find through unique extraction, process for refining it is the Blume plant extract that can obtain being rich in the Pai Lixin derivant to separation purifying technique.
The present invention also provides pharmaceutical composition and preparation and the application of said Blume plant extract in health product and pharmaceutical field that contains Blume plant extract; Particularly in the health product of preparation vascular dementia disease and the application in the medicine; Pai Lixin derivant total content is more than 35% in the said Blume plant extract; Preferred Pai Lixin derivant total content is more than 50%; More preferably Pai Lixin derivant total content is 50%-95%, and preferred said Pai Lixin derivant is parishin A, B, C.Wherein percentage ratio % is without special instruction, and % all is weight percentage.
The present invention assigns upright hot derivant structure general formula following:
Wherein, R
1, R
2Be selected from independently of one another with R3:
Deng;
R4 is selected from hydrogen, C1-C6 alkyl (preferable methyl; Ethyl; Propyl group, second propyl group, butyl; Isobutyl group); C1-C6 alkyl phenyl (preferred benzyl), to hydroxybenzyl, or
etc.;
Glu representes β-D-glucopyranosyl, and Me representes methyl.
The process that the present invention prepares said Blume plant extract is following:
1. method for distilling: plant Rhizoma Gastrodiae (tuber) is pulverized; Use the aqueous solution of 20-100% (wherein preferred 50-95%) C1-C6 alkylol to extract down in the temperature (temperature of preferred room temperature to solvent refluxing) of 0 ℃-solvent refluxing as solvent then, extracting solution gets extractum through normal pressure or concentrating under reduced pressure; Wherein said C1-C6 alkylol is preferably the mixed solvent that methanol, ethanol, isopropyl alcohol or n-butyl alcohol or their are formed, wherein more preferably methanol, ethanol.
2. process for purification:
Extractum is refining with chromatographic process, purification are used the eluting solvent eluting, collect the stream part of being rich in parishin A, B, C compounds, concentrate, and filter, and drying detects and collect the plant extract that is rich in the Pai Lixin derivant.
Wherein saidly be used to make with extra care, the chromatographic process of purification is macroporous adsorbent resin chromatography, purification on normal-phase silica gel and reverse phase silica gel chromatograph; Perhaps their combination; The extractum that perhaps extraction is obtained is mixed in silica gel or the kieselguhr, dries the back with the eluting solvent eluting that refluxes; Said eluting solvent is a water, the C1-C6 alkylol, as: methanol, ethanol, isopropyl alcohol or n-butyl alcohol etc.; Halogenated hydrocarbons, as: dichloromethane, chloroform (chloroform) etc., ether solvent; As: ether, methyl tert-butyl ether etc., ketones solvent, as: acetone, 2-butanone etc.; Esters solvent; Like ethyl acetate, Ethyl formate etc., and by the mixed solvent of above-mentioned solvent composition, wherein preferred eluting solvent is a kind of or several mixed solvents in chloroform (chloroform), ethyl acetate, ethanol, the first alcohol and water.In the said process for purification, when making with extra care with styrene tyle macroporous adsorption resin, eluting solvent is preferably ethanol or the methanol aqueous solution of water and 10-75%; When with the reverse phase silica gel chromatographic refining, eluting solvent is preferably ethanol or the methanol aqueous solution of water and 10-50%; When making with extra care with purification on normal-phase silica gel, eluting solvent is preferably the mixed solvent of chloroform or ethyl acetate and 90-100% ethanol water or methanol composition, and their ratio is preferably 10: 1-2: 1.
In the wherein said method for preparing, the stream part of being rich in parishin A, B, C compounds is detected through thin layer chromatography (TLC), ultraviolet (UV), HPLC methods such as (HPLC), wherein preferred HPLC detection method.
The total content of Pai Lixin derivant detects through the HPLC method in the Blume plant extract that preferred the present invention obtains.Preferably use the high performance liquid chromatogram external standard method, make standard, calculate the wherein total content of Pai Lixin compounds with parishin A.
Pai Lixin derivant total content is more than 25% in the Blume plant extract that obtains according to the method described above; Preferred Pai Lixin derivant total content is more than 50%; More preferably Pai Lixin derivant total content is 50%-95%, and preferred said Pai Lixin derivant is parishin A, B, C.
The Blume plant extract that contains the Pai Lixin derivant that obtains according to the method described above has the effect of Fructus Alpiniae Oxyphyllae, hypermnesis.
The method for preparing of introduction of the present invention provides a kind of in the Blume plant extract method for preparing with high-load Pai Lixin derivant, and does not mean that the Blume plant extract that has only the high-load Pai Lixin derivant that obtains through said method could be used as the medicine of disease such as preparation treatment of vascular dementia.Can infer, those skilled in the art also can have same drug effect with the Blume plant extract that is rich in the Pai Lixin derivant that additive method obtains.
Prepare the plant extract in the Chinese medicine Rhizoma Gastrodiae with above extraction and process for purification, wherein effective ingredient-the content of Pai Lixin derivant in plant extract can be up to more than 50%.Wherein the macroporous adsorbent resin method is refining is more suitable in suitability for industrialized production.
The plant extract that utilizes the inventive method to obtain can be processed pharmaceutical preparation with pharmaceutically acceptable carrier, for example: injection, tablet, capsule, oral liquid or drop pill etc.When the plant extract that utilizes the inventive method to obtain prepares the various dosage form of required medicine, can be according to the conventional production method preparation of pharmaceutical field.Preferred this type pharmaceutical preparation of the present invention can be by oral, parenteral.Preferred formulation is oral or intravenous administration.
The sterile injectable form of the present composition can be aqueous or oiliness suspensoid.These suspensoids can be prepared according to technology known in the art, the dispersion that utilize to be fit to or wetting agent and suspending agent.Aseptic injectable formulation can also be at nontoxic parenteral acceptable diluent or sterile injectable solution agent or the suspensoid in the solvent, the for example solution in 1,3 butylene glycol.Acceptable carrier that can adopt and solvent have water, Ringer's mixture and isoosmotic sodium chloride solution.In addition, aseptic expressed oi also often is used as solvent or suspension media.For this reason, can adopt the expressed oi of any gentleness, comprise synthetic list-or two-glyceride.Fatty acid, for example oleic acid and glyceride ester derivatives thereof can be used for preparing injection, and they are natural pharmaceutically acceptable oil, for example olive oil or Oleum Ricini, especially their polyoxy ethylization form.These oily solution or suspensoid can also contain long-chain alcohol diluent or dispersant, for example carboxymethyl cellulose or similar dispersant, and they generally are used to prepare pharmaceutically acceptable dosage form, comprise Emulsion and suspensoid.From the purpose of preparation, can also use other surfactants commonly used, for example Tweens, spans and other emulsifying agents or bioavailability reinforcing agent, they generally are used in the manufacturing of pharmaceutically acceptable solid, liquid or other dosage forms.
Pharmaceutical composition of the present invention can include but not limited to capsule, tablet, aqueous suspension or solution by any oral acceptable forms oral administration.Under the situation of mouth with tablet, carrier commonly used comprises lactose and corn starch.Usually also add lubricant, for example magnesium stearate.With regard to regard to the oral capsule administration, useful diluent comprises lactose and exsiccant corn starch.Very moment is during with the needs aqueous suspension, active component and emulsifying and suspending agent coupling.If necessary, can also add some sweeting agent, correctives or coloring agent.
If necessary, in case patient's condition makes moderate progress, can give the maintenance dose of The compounds of this invention, compositions or combination.Subsequently, can reduce dosage or frequency or the dosage of administration and the level that frequency is able to keep to the condition of having improved,, should stop treatment when symptom has alleviated to desired level according to symptom.But, in case disease symptoms has any recurrence, the patient possibly accept intermittent treatment on long-term basis.
Can also comprise other activating agents that are used to treat vascular dementia in the pharmaceutical preparation of the present invention or with the medicine or the order administration of other treatment vascular dementia.
It is to be further understood that; Any specific patient's concrete dosage and treatment system will depend on multiple factor, comprise activity, age, body weight, general health situation, sex, diet, administration time, discharge rate, drug regimen, the attending doctor's of the concrete extract that is adopted judgement and the seriousness of the specified disease of being treated.
The specific embodiment
Following preparation embodiment and EXPERIMENTAL EXAMPLE can further specify the present invention, but do not limit the present invention in any way.
Embodiment 1:
1. extract: Chinese medicine Rhizoma Gastrodiae medical material 1kg, pulverize the back and add 50% soak with ethanol extraction 3 times, each 24 hours.Merge extractive liquid, reclaims ethanol and also is concentrated into thick extractum, adds the distilled water heating for dissolving, is cooled to room temperature, leaves standstill 24 hours, centrifugally gets rid of filter, clear filtrate.
2. refining: above-mentioned filtrating is through treated HPD-100 type macroporous adsorbent resin; Water and 10%, 20%, 30%, 40%, 50%, 75% ethanol gradient elution; HPLC detects, and collects the stream part of being rich in the Pai Lixin compounds, merges; Concentrating under reduced pressure, spray drying promptly get plant extract 4.48g.Through high effective liquid chromatography for measuring, wherein the Pai Lixin kind compound content is 51.8%.
Embodiment 2:
1. extract: Chinese medicine Rhizoma Gastrodiae medical material 1kg, to pulverize the back and add 50% ethanol, 50 ℃ of warm macerating bubbles extract each 6 hours 3 times.Merge extractive liquid, reclaims ethanol and also is concentrated into thick extractum, adds the distilled water heating for dissolving, is cooled to room temperature, leaves standstill 24 hours, centrifugally gets rid of filter, clear filtrate.
2. refining: above-mentioned filtrating is through treated HP-20 type macroporous adsorbent resin; Water and 10%, 20%, 30%, 40%, 50%, 75% ethanol gradient elution; HPLC detects, and collects the stream part of being rich in the Pai Lixin compounds, merges; Concentrating under reduced pressure, spray drying promptly get plant extract 4.42g.Through high effective liquid chromatography for measuring, wherein the Pai Lixin kind compound content is 52.6%.
Embodiment 3:
1. extract: Chinese medicine Rhizoma Gastrodiae medical material 1kg, after adding 50% soak with ethanol is spent the night after pulverizing, heating and refluxing extraction 3 times, each 3.0 hours.Merge extractive liquid, reclaims ethanol and also is concentrated into thick extractum, adds the distilled water heating for dissolving, is cooled to room temperature, leaves standstill 24 hours, centrifugally gets rid of filter, clear filtrate.
2. refining: above-mentioned filtrating is through treated HP-20 type macroporous adsorbent resin; The methanol of water, 10%, 20%, 30%, 40%, 50% and 75% concentration gradient is successively washed; HPLC detects, and collects the stream part of being rich in the Pai Lixin compounds, merges; Concentrating under reduced pressure, spray drying promptly get plant extract 4.68g.Through high effective liquid chromatography for measuring, wherein the Pai Lixin kind compound content is 54.4%.
Embodiment 4:
1. extract: Chinese medicine Rhizoma Gastrodiae medical material 1kg, pulverize the back and add 75% ethanol, room temperature lixiviate 3 times, each 24.0 hours.Merge extractive liquid, reclaims ethanol and also is concentrated into thick extractum, adds the distilled water heating for dissolving, is cooled to room temperature, leaves standstill 24 hours, centrifugally gets rid of filter, clear filtrate.Concentrating under reduced pressure gets concentrated solution.
2. make with extra care: concentrated solution passes through reverse phase silica gel post (C-18), behind water and the 10% alcoholic solution eluting, and the alcoholic solution eluting of reuse 50% concentration, HPLC detects, and collects the stream part of being rich in the Pai Lixin compounds, merges concentrating under reduced pressure, the dry plant extract 2.18g that gets.Through high effective liquid chromatography for measuring, wherein the Pai Lixin kind compound content is 66.2%.
Embodiment 5:
1. extract: Chinese medicine Rhizoma Gastrodiae medical material 1kg after the pulverizing, adds after 75% soak with ethanol spends the night 75 ℃ of heating lixiviates 3 times, each 6.0 hours.Merge extractive liquid, reclaims ethanol and is concentrated into thick extractum.
2. refining: the extractum silica gel mixed sample, through purification on normal-phase silica gel (100-200 order) chromatographic column, behind chloroform-methanol (9: the 1) eluting; Reuse chloroform-methanol (5: 1) eluting, HPLC detects, and collects the stream part of being rich in the Pai Lixin compounds; Merge concentrating under reduced pressure, the dry plant extract 4.51g that gets.Through high effective liquid chromatography for measuring, wherein the Pai Lixin kind compound content is 50.3%.
Embodiment 6:
1. extract: Chinese medicine Rhizoma Gastrodiae medical material 1kg after the pulverizing, adds after 75% soak with ethanol spends the night heating and refluxing extraction 3 times, each 3.0 hours.Merge extractive liquid, reclaims ethanol and is concentrated into thick extractum.
2. refining: the extractum silica gel mixed sample, through purification on normal-phase silica gel (100-200 order) post, behind ethyl acetate-95% ethanol (10: the 1) eluting; Reuse ethyl acetate-95% ethanol (3: 1) and ethyl acetate-95% ethanol (2: 1) is eluting successively; HPLC detects, and collects the stream part of being rich in the Pai Lixin compounds, merges; Concentrating under reduced pressure, the dry plant extract 4.88g that gets.Through high effective liquid chromatography for measuring, wherein the Pai Lixin kind compound content is 56.0%.
Embodiment 7:
1. extract: Chinese medicine Rhizoma Gastrodiae medical material 1kg, pulverize the back and add 95% ethanol room temperature lixiviate 3 times, each 24.0 hours.Merge extractive liquid, reclaims ethanol and also is concentrated into thick extractum, adds the distilled water heating for dissolving, is cooled to room temperature, leaves standstill 24 hours, centrifugally gets rid of filter, clear filtrate.Concentrating under reduced pressure gets concentrated solution.
2. make with extra care: concentrated solution passes through reverse phase silica gel (C-18) post, behind water and the 10% alcoholic solution eluting, and the alcoholic solution eluting of reuse 50% concentration, HPLC detects, and collects the stream part of being rich in the Pai Lixin compounds, merges concentrating under reduced pressure, the dry plant extract 1.69g that gets.Through high effective liquid chromatography for measuring, wherein the Pai Lixin kind compound content is 60.9%.
Embodiment 8:
1. extract: Chinese medicine Rhizoma Gastrodiae medical material 1kg, after the pulverizing, add 95% ethanol, 75 ℃ of warm macerating extract each 8.0 hours 3 times.Merge extractive liquid, reclaims ethanol and is concentrated into thick extractum.
2. refining: the extractum silica gel mixed sample, through purification on normal-phase silica gel (100-200 order) post, behind chloroform-methanol (9: the 1) eluting; Reuse chloroform-methanol (5: 1) eluting, HPLC detects, and collects the stream part of being rich in the Pai Lixin compounds; Merge concentrating under reduced pressure, the dry plant extract 1.22g that gets.Through high effective liquid chromatography for measuring, wherein the Pai Lixin kind compound content is 55.1%.
Embodiment 9:
1. extract: Chinese medicine Rhizoma Gastrodiae medical material 1kg after the pulverizing, adds after 95% soak with ethanol spends the night heating and refluxing extraction 3 times, each 4.0 hours.Merge extractive liquid, reclaims ethanol and is concentrated into thick extractum.
2. refining: the extractum silica gel mixed sample, through purification on normal-phase silica gel (100-200 order) post, behind ethyl acetate-95% ethanol (10: the 1) eluting; Reuse ethyl acetate-95% ethanol (5: 1) and ethyl acetate-95% ethanol (3: 1) eluting; HPLC detects, and collects the stream part of being rich in the Pai Lixin compounds, merges; Concentrating under reduced pressure, the dry plant extract 1.86g that gets.Through high effective liquid chromatography for measuring, wherein the Pai Lixin kind compound content is 55.8%.
EXPERIMENTAL EXAMPLE
Blume plant extract is for the influence of intending vascular dementia rat space learning memory ability
The abbreviation of hereinafter adopting " clb " is meant that parishin A, B, C and/or its derivative content are greater than 50% Rhizoma Gastrodiae extract.
The observation of ability of learning and memory is an indispensable important indicator in the dull-witted clinical experimental research with estimating; This experiment is specially selected the water maze that is usually used in detecting the animal learning memory ability in the world for use in order to estimate the ability of learning and memory of medicine to animal pattern objectively.Its detection be rat in training repeatedly, the hidden platform of fixed position is sought by association, it is cognitive to form stable locus, this spatial cognition be a kind of with different I be reference the cognition of reference point, formed memory is that a kind of georeferencing is remembered.From information Processing and extracting mode; This georeferencing memory gets into awareness system; The mechanism of its storage relates generally to limbic system (like Hippocampus) and the relevant brain of cerebral cortex district; Should belong to declarative memory, and clinical forgetful and dull-witted patient, declarative memory is at first impaired and more outstanding just.So from the memory attribute that detects, the screening study that utilization Morris water maze is prevented and treated this type of disease active drug is more appropriate.
1. experiment material
Experimental drug: be the sample (clb) that is obtained among the preparation embodiment 1, code name 1210-A.
A laboratory animal cleaning level SD rat, male, body weight 190-210g is supplied with by Beijing Vital River Experimental Animals Technology Co., Ltd., and the quality certification number is scxk (capital) 2002-0003.Nature diet under the experiment condition experimentized after conforming three days.
Instrument Morris water maze DMS-2 system is provided by Chinese Academy of Sciences institute of materia medica
2. experimental technique
2.1 intend the preparation of vascular dementia rat model
Male SD rat, body weight 190-210g, 10% chloral hydrate intraperitoneal injection of anesthesia, it is fixing to lie on the back, and throat portion QUMAO sterilization tailing edge medisection is separated bilateral common carotid arteries, cuts off sew up wound after the dual silk thread ligation.The only free bilateral common carotid arteries of sham operated rats, each is organized rat and raises with condition.
2.2 laboratory animal is divided into groups
Animal is divided into dose groups (n=15), positive drug donepezil group (n=15), positive drug nimodipine group (n=15) among sham operated rats (n=10), model group (n=15), 1210-A small dose group (n=15), the heavy dose of group of 1210-A (n=15), the 1210-A at random.
2.3 administration
Postoperative administration in 24 hours, 1210-A small dose group rat are pressed the heavy dose of group of 0.8mg/kg, 1210-A rat and are pressed among 7.5mg/kg, the 1210-A dose groups rat and press the 2.5mg/kg gastric infusion; Positive drug donepezil group is pressed 0.58mg/kg, the nimodipine group is pressed the 9mg/kg gastric infusion.Sham operated rats and model group animal are irritated stomach and the capacity normal saline such as give.Successive administration 40 days carried out the training of Morris water maze from the 42nd day.
The Morris water maze is mainly by round pool with videotape automatically and the computer for analysis system forms; Through the camera system of top, labyrinth the heuristic process of rat in the labyrinth being carried out whole process takes; Like the movement locus of rat, movement time, move distance, motion mode etc., avoided artificial factor.Platform is placed on Southwest Quadrant (III quadrant) center apart from pool wall 22cm place, before the test water is injected the pond, depth of water 30cm (be that the water surface exceeds platform surface 1cm, make rat can not see platform), and water temperature is controlled between 20-21 ℃, 25 ℃ of room temperatures.Require various experiment conditions to remain unchanged during experiment.Whole experiment is divided into hides flat acquisition experiment (hidden-platformacquisition training) and space search experiment (probetrial testing) two parts of closing.
EXPERIMENTAL EXAMPLE 1: to intending the influence of vascular dementia rat orientation navigation test escape latency
The result sees table 1.It is shorter and shorter through the time of swimming instruction searching platform that each organizes rat; 1st, 2 days each treated animal escape latency are not seen notable difference; Obviously prolong (P＜0.05) since the 3rd day swimming instruction model group rat escape latency than sham operated rats, explain that there are tangible space learning dysmnesia in rat model; Each dose groups rat escape latency of 1210-A all has minimizing, particularly small dose group in various degree obviously to shorten (P＜0.05) than model group in 3,4 days in swimming than the model group rat; The positive drug nimodipine also obviously shortened (P＜0.05) than model group on the 4th day in swimming.
Table 1. medicine is to the influence of intending vascular dementia rat Morris water maze escape latency ((x ± s)
Annotate: compare with model group:
*P＜0.05
EXPERIMENTAL EXAMPLE 2: to intending the influence in vascular dementia rat orientation navigation test swimming path
The result sees table 2.Path through each treated animal searching platform of swimming instruction is swum is shorter and shorter; Each is organized the path of rat swimming instruction in the 1st, 2 days and is not seen notable difference; But since swimming instruction in the 3rd day, swimming path of model group rat and the apparent in view prolongation of sham operated rats (P＜0.05); Each dose groups swimming path of 1210-A all has in various degree than the model group rat reduces, and particularly small dose group obviously shortened (P＜0.05) than model group in 3,4 days in swimming.
Table 2. medicine is to the influence of intending vascular dementia rat Morris water maze swimming instruction swimming path (x ± s)
Annotate: compare with model group:
*P＜0.05
EXPERIMENTAL EXAMPLE 3: to intending the influence of vascular dementia rat Morris water maze space exploration ability
Space exploration test through record remove respectively organize behind the platform in the labyrinth rat in time, the path of the motion of original platform quadrant and the number of times that accurately passes the original platform position reflect that rat is through the spatial memory ability of preceding 10 swimming instructions to platform.If animal has formed stronger memory to platform in the locus of water maze really, when being placed in the labyrinth once more, can near the original platform in-scope, on purpose seek platform.This experimental result demonstration, after training, each organizes rat does not have notable difference at platform quadrant swimming time and the ratio (tP/tT) of total swimming time and the swimming of platform quadrant apart from the ratio (dP/dT) that accounts for total swimming distance.But the model group rat is compared the number of times that accurately passes through the original platform position and obviously reduces (P＜0.05) with sham operated rats, explains that the spatial memory ability suffers damage.1210-A respectively organizes rat and accurately passes through the number of times of original platform position and than model group raising is in various degree arranged all, particularly small dose group obvious difference (P＜0.05).
Table 3.1210-A is to the influence of intending vascular dementia rat Morris water maze space exploration ability (x ± s)
Annotate: compare with model group:
*P＜0.05.
Claims (8)
1. the Blume plant extract purposes in the medicine of preparation treatment of vascular dementia disease; Pai Lixin derivant total content is more than 35% in the wherein said plant extract; Said derivant is a kind of monomeric compound of Pai Lixin derivant, perhaps is the mixture of any multiple chemical compound in the Pai Lixin derivant; Said Pai Lixin derivant structure general formula is following:
Wherein, R
1, R
2Be selected from independently of one another with R3:
R4 is selected from hydrogen, C1-C6 alkyl; The C1-C6 alkyl phenyl; To hydroxybenzyl,
or
Glu representes β-D-glucopyranosyl, and Me representes methyl.
2. according to the purposes of claim 1, wherein said R4 is selected from methyl, ethyl, propyl group, second propyl group, butyl, isobutyl group or benzyl.
3. according to the purposes of claim 1, wherein said Pai Lixin derivant total content is more than 50%.
4. according to the purposes of claim 1, wherein said Pai Lixin derivant total content is 50%-95%.
5. according to each purposes of claim 1-4, wherein said Pai Lixin derivant is parishin A, B or C, and wherein the structural formula of A, B, C is following:
6. the purposes of Pai Lixin derivant in the medicine of preparation vascular dementia disease, said derivant is a kind of monomeric compound of Pai Lixin derivant, perhaps is the mixture of any multiple chemical compound in the Pai Lixin derivant; Said Pai Lixin derivant structure general formula is following:
Wherein, R
1, R
2Be selected from independently of one another with R3:
R4 is selected from hydrogen, C1-C6 alkyl; The C1-C6 alkyl phenyl; To hydroxybenzyl,
or
Glu representes β-D-glucopyranosyl, and Me representes methyl.
7. according to the purposes of claim 6, wherein said R4 is selected from methyl, ethyl, propyl group, second propyl group, butyl, isobutyl group or benzyl.
8. according to the purposes of claim 6 or 7, wherein said Pai Lixin derivant is parishin A, B or C, and wherein the structural formula of parishin A, B, C is following:
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| WO2011140676A1 (en) * | 2010-05-12 | 2011-11-17 | 北京科莱博医药开发有限责任公司 | Rhizoma gastrodiae plant extract used to prevent and treat alzheimer disease and vascular dementia and mixed type diseases thereof and preparative method thereof |
| CN103588830A (en) * | 2013-06-07 | 2014-02-19 | 江西本草天工科技有限责任公司 | New benzyl alcohol ester glycoside compound in gastrodia elata and application thereof |
| CN103626812B (en) * | 2013-12-10 | 2016-03-30 | 江西本草天工科技有限责任公司 | Gloomy glycosides compound of a kind of new Bali and uses thereof in rhizoma Gastrodiae |
| CN104706656B (en) * | 2013-12-13 | 2018-07-13 | 中国科学院大连化学物理研究所 | A kind of Rhizoma Gastrodiae extract or composition for preventing dementia |
| CN105726551A (en) * | 2016-01-28 | 2016-07-06 | 浙江大学 | Application of plant extract parishin of gastrodia elata in preparing anti-aging medicine |
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| CN1977951A (en) * | 2005-12-02 | 2007-06-13 | 北京科莱博医药开发有限责任公司 | Gastrodia elata plant extract for preventing senile dementia and its preparing method |
| CN101143192A (en) * | 2006-04-07 | 2008-03-19 | 中央研究院 | Therapeutic gastrodia extracts |
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| CN101143192A (en) * | 2006-04-07 | 2008-03-19 | 中央研究院 | Therapeutic gastrodia extracts |
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